RESUMO
PURPOSE: An antibody-drug conjugate consisting of monomethyl auristatin E (MMAE) conjugated to the anti-CD30 monoclonal antibody (mAb) cAC10, with eight drug moieties per mAb, was previously shown to have potent cytotoxic activity against CD30(+) malignant cells. To determine the effect of drug loading on antibody-drug conjugate therapeutic potential, we assessed cAC10 antibody-drug conjugates containing different drug-mAb ratios in vitro and in vivo. EXPERIMENTAL DESIGN: Coupling MMAE to the cysteines that comprise the interchain disulfides of cAC10 created an antibody-drug conjugate population, which was purified using hydrophobic interaction chromatography to yield antibody-drug conjugates with two, four, and eight drugs per antibody (E2, E4, and E8, respectively). Antibody-drug conjugate potency was tested in vitro against CD30(+) lines followed by in vivo xenograft models. The maximum-tolerated dose and pharmacokinetic profiles of the antibody-drug conjugates were investigated in mice. RESULTS: Although antibody-drug conjugate potency in vitro was directly dependent on drug loading (IC(50) values E8Assuntos
Anticorpos Monoclonais/imunologia
, Imunoconjugados/imunologia
, Linfoma Difuso de Grandes Células B/imunologia
, Oligopeptídeos/farmacologia
, Animais
, Anticorpos Monoclonais/farmacocinética
, Anticorpos Monoclonais/farmacologia
, Humanos
, Imunoconjugados/farmacocinética
, Imunoconjugados/farmacologia
, Antígeno Ki-1/imunologia
, Linfoma Difuso de Grandes Células B/patologia
, Dose Máxima Tolerável
, Camundongos
, Oligopeptídeos/farmacocinética
, Transplante Heterólogo
, Células Tumorais Cultivadas